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There are two estrogen receptors, namely α and β. Both receptors bind estrogen with the same affinity, are expressed in the heart and vasculature, and have various functions (Mendelsohn and Karas 1999). Studies have been conducted to assess the function and possible cardioprotective mechanisms of the two estrogen receptors (Figure 1). Certain studies favour estrogen α-receptors while other studies emphasize estrogen β-receptors as the cardioprotective receptors. The two receptors are discussed below in the context of research that has been conducted to date.

1.3.1.1 Estrogen α-receptors

The main effects of estrogen α-receptors (ER-α) are on the vasculature. The functions mediated by ER-α are the protection of damaged blood vessels by enhancing re-endothelialization, decreasing atherosclerotic plaque formation and inhibiting smooth muscle cell proliferation and matrix deposition (Mendelsohn and Karas 2005). In addition, ER-α interact with cytoplasmic proteins, are important in cardiomyocyte structure and stability, and play a role in cell-cell interactions (Mahoodzadeh et al 2006). ER-α are reported to be up-regulated during aortic stenosis and dilated cardiomyopathy (Mahoodzadeh et al 2006).

Interestingly, Mahoodzadeh S et al (2006) revealed that dilated cardiomyopathy in both genders invokes mRNA up-regulation of ER-α. In addition, alterations in the localisation of these receptors occur, such that there is a loss of ER-α from the intercalated discs and a co-localization with β-catenin. It has therefore been postulated that the up-regulation of ER-α

Figure 1: Beneficial effects mediated by estrogen receptors (α and β) on cardiomyocytes

may be a possible cardioprotective mechanism in response to dilated cardiomyopathy and aortic stenosis. Furthermore, during heart failure, the stability of the intercalated discs is weakened, and therefore ER-α are up-regulated and their localisation is altered to cope with the extra load exerted on the heart (Mahoodzadeh et al 2006).

The effects of ER-α on post-ischaemic myocardial function, inflammatory signals and apoptotic signalling have also been evaluated (Wang et al 2006). In a study comparing ER-α knockout mice of either gender to wild type mice, the male wild type mice as well as the ER-α knockout mice of either gender had myocardial contractile dysfunction; whereas the female wild type mice had no myocardial functional impairment. It is important to note that the female wild type (who had normal cycling endogenous estrogen), had lower levels of the pro-apoptotic protein, JNK and elevated levels of extracellular signal-regulated protein kinase (ERK), which assists in myocardial functional recovery after ischaemic reperfusion injury.

In this regard, Booth et al (2005) demonstrated the cardioprotective effects of ER-α in an ischaemic-reperfusion model (LAD coronary artery ligation for 30 minutes followed by reperfusion). Intact rabbits as well as ovariectomised female rabbits were used in the study.

Three groups of rabbits were used: group 1 consisted of intact rabbits receiving ER-α agonist, estrogen β-receptor (ER-β) agonist, 17 β-estradiol, and vehicle; group 2 consisted of intact rabbits receiving ER antagonist+ ER-α agonist, ER antagonist + 17β-estradiol, and ER antagonist + vehicle; group 3 consisted of ovariectomized female rabbits and received the same regimen as group 1. The results demonstrated that infarct sizes were smaller in intact rabbits treated with ER- α agonist and 17β-estradiol but not ER-β agonist. In addition, ER- α agonist and 17β-estradiol treated rabbits had similar infarct sizes when treated with the ER antagonist, thus highlighting the cardioprotective effects of estrogen and more specifically ER-α. The results also revealed that ER-α agonist and 17β-estradiol treated rabbits had decreased levels of C-reactive Protein (CRP) and cardiac-specific Troponin I (cTn1);

markers of myocardial damage, an effect not observed in the ER- β agonist treated rabbits.

These results suggest that the cardioprotective effects of estrogen are mediated by estrogen α-receptors but not by estrogen β-α-receptors. Interestingly, ovariectomized female rabbits treated with vehicle had larger infarct sizes as compared to intact female rabbits also receiving vehicle after ischemic-reperfusion. The latter emphasises the cardioprotective effects of endogenous estrogen.

A further study confirmed that the cardioprotective effects of estrogen are mediated by ER- α (Jeanes et al 2008). In ovariectomised rats an ER-α agonist significantly reduced infarct size (in an ischaemic-reperfusion model induced by LAD coronary artery ligation followed by reperfusion) and oxidative stress. In comparison an ER-β antagonist produced no effect on the ischaemia-induced myocardial injury. The lack of effect of the ER-β antagonist (Jeanes et al 2008) in combination with data showing no effect of ER-β agonist on infarct size (Booth et al 2005), suggests that ER-β play no role in myocardial ischaemia reperfusion injury. However, there is still a possibility that ER-β may be cardioprotective in other models of CVS diseases.

1.3.1.2 Estrogen β-receptors

Estrogen β-receptors (ER-β) have been shown to play a role in vasodilatation and the control of blood pressure in both genders (Mendelsohn and Karas 2005). In addition, the role of ER-β in the development of chronic heart failure after MI (LAD coronary artery ligation) has been demonstrated in ovariectomised ER-β knockout mice. Eight weeks after the MI, mortality rates were higher in the ovariectomised ER-β knockout mice compared to wild-type mice; however, no differences in infarct size, cardiac geometry or function (hemodynamic and echocardiographic results) were noted between the groups. The higher mortality rates in the ovariectomised ER-β knockout mice were associated with increases in body weight, pleural effusions, ascites, atrial naturetic peptide levels and phospholamban expression; all of

which are markers of heart failure. Hence, although ER-β have no effect on infarct size either after MI (Pelzer et al 2005) or in an ischaemic-reperfusion model (Booth et al 2005), ER-β demonstrates cardioprotective effects with regards to the development of heart failure. In addition, ER-β, but not ER-α, prevent increases in pressure-overload (via TAC) induced hypertrophy (Skavdahl et al 2004). Interestingly, the increase in pressure-overload induced hypertrophy as a consequence of ER-β knockout was noted in female but not in male mice (Skavdahl et al 2004). In addition, male mice had significantly increased pressure-overload induced hypertrophy compared to female mice, hence highlighting the underlying cardioprotective effects of endogenous estrogen mediated by the ER-β.

Additional cardiovascular effects noted to be mediated by ER-β include decreases in lipoprotein lipase expression (and hence fatty acid metabolism) (Skavdahl et al 2004).

Moreover, ER-β knockout mice were shown to have prolonged ventricular repolarisation, decreased ventricular spontaneity and decreased expression of the voltage-gated potassium channels (Korte et al 2005). These effects mediated by ER-β may explain the decreased incidence of fatal ventricular tachyarrhythmias in women compared to men (Coa et al 2000).

In summary, both estrogen receptors play a role in cardioprotection. However these roles differ in that the ER-α maintain myocardial contractility, inhibit apoptotic signalling, decrease oxidative stress and reduce myocardial infarct size (Pelzer et al 2005; Booth et al 2005; Jeanes et al 2008; Mahoodzadeh et al 2006); whereas ER-β decrease mortality in chronic heart failure, pressure overload hypertrophy, lipoprotein lipase and tachyarrythmias (Skavdahl et al 2004; Korte et al 2005). Neither receptor has been established as being more important with regards to cardioprotection; however the interaction of these receptors with other physiological systems such as the SNS may differ.